Effects of continuously enhanced corticotropin releasing factor expression within the bed nucleus of the stria terminalis on conditioned and unconditioned anxiety

The lateral division of the bed nucleus of the stria terminalis (BNST), which forms part of the circuitry regulating fear and anxiety, contains a large number of neurons expressing corticotropin releasing factor (CRF), a neuropeptide that has a prominent role in the etiology of fear-and anxiety-related psychopathologies. Stress increases CRF expression within BNST neurons, implicating these cells in stress-and anxiety-related behaviors. These experiments examined the effect of chronically enhanced CRF expression within BNST neurons on conditioned and unconditioned anxiety-related behavior by using a lentiviral vector containing a promoter that targets CRF gene overexpression (OE) to CRFergic cells. We found that BNST CRF-OE did not affect unconditioned anxiety-like responses in the elevated plus maze or basal acoustic startle amplitude. CRF-OE induced before training weakened sustained fear (conditioned anxiety); when induced after conditioning, CRF-OE increased expression of the conditioned emotional memory. Increased BNST CRF expression did not affect plasma corticosterone concentration but did decrease CRFR1 receptor density within the BNST and CRFR2 receptor density within the dorsal portion of the caudal dorsal raphe nucleus. These data raise the possibility that the observed behavioral effects may be mediated by enhanced CRF receptor signaling or compensatory changes in CRF receptor density within these structures. Together, these studies demonstrate that CRF neurons within the lateral BNST modulate conditioned anxiety-like behaviors and also suggest that enhanced CRF expression within these neurons may contribute to inappropriate regulation of emotional memories. Molecular Psychiatry (2013) 18, 308-319; doi: 10.1038/mp. 2011.188; published online 31 January 2012